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Effects of Digesting Chondroitin Sulfate Proteoglycans on Plasticity in Cat Primary Visual Cortex

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Effects of Digesting Chondroitin Sulfate Proteoglycans on Plasticity in Cat Primary Visual Cortex 234 • The Journal of Neuroscience, January 2, 2013 • 33(1):234–243 Development/Plasticity/Repair Effects of Digesting Chondroitin Sulfate Proteoglycans on Plasticity in Cat Primary Visual Cortex Vasily Vorobyov,1 Jessica C.F. Kwok,3 James W. Fawcett,3 and Frank Sengpiel1,2 1School of Biosciences and 2Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff CF10 3AX, United Kingdom, and 3Cambridge University Centre for Brain Repair, Cambridge CB2 0PY, United Kingdom Monocular deprivation (MD) during a critical period of postnatal development produces significant changes in the anatomy and physi- ology of the visual cortex, and the deprived eye becomes amblyopic. Extracellular matrix molecules have a major role in restricting plasticity such that the ability to recover from MD decreases with age. Chondroitin sulfate proteoglycans (CSPGs) act as barriers to cell migration and axon growth. Previous studies showing that degradation of CSPGs by the bacterial enzyme chondroitinase can restore plasticity in the adult rat visual cortex suggest a potential treatment for amblyopia. Here MD was imposed in cats from the start of the critical period until 3.5 months of age. The deprived eye was reopened, the functional architecture of the visual cortex was assessed by optical imaging of intrinsic signals, and chondroitinase was injected into one hemi- sphere. Imaging was repeated 1 and 2 weeks postinjection, and visually evoked potentials (VEPs) and single-cell activity were recorded. Immunohistochemistry showed that digestion of CSPGs had been successful. After 2 weeks of binocular exposure, some recovery of deprived-eyeresponsesoccurredwhenchondroitinasehadbeeninjectedintothehemispherecontralateraltothateye;wheninjectedinto the ipsilateral hemisphere, no recovery was seen. Deprived-eye VEPs were no larger in the injected hemisphere than in the opposite hemisphere. The small number of neurons dominated by the deprived eye exhibited poor tuning characteristics. These results suggest that despite structural effects of chondroitinase in adult cat V1, plasticity was not sufficiently restored to enable significant functional recovery of the deprived eye. Introduction protein core with one or more glycosaminoglycan (GAG) chains Amblyopia (“lazy eye”) is the commonest disorder of vision in attached. Chondroitin sulfate proteoglycans (CSPGs) act as bar- children. It is usually treated by refractive adaptation, followed by riers to cell migration (Mizuguchi et al., 2003), axon growth either occlusion (patching) therapy or defocus by atropinization (Becker and Becker, 2002), and plasticity, mostly through their of the good eye, thus disadvantaging it for a time to enforce the GAG chains. use of the amblyopic eye (Stewart et al., 2011). The effectiveness During postnatal development, CSPGs accumulate in partic- of this procedure decreases with age and is typically limited be- ular around inhibitory interneurons, contributing to the forma- yond 8 years. Recently, an increasing number of studies has tion of “perineuronal nets” (PNNs) (Celio et al., 1998). These aimed at treating amblyopia in adulthood by means of restoring structures appear to restrict plasticity in the adult brain (Hock- visual cortical plasticity (Bavelier et al., 2010). field et al., 1990). In the visual cortex, their appearance coincides Adult cortical plasticity is suppressed both at a functional with the end of the critical period (Lander et al., 1997), and dark level, through the balance of excitation and inhibition, and at a rearing from birth delays not only the critical period but also the structural level, through inhibition of dendritic motility and neu- expression of antigens associated with PNNs (Guimara˜es et al., rite growth (Hensch, 2005). The maturation of the extracellular 1990). Mice with attenuated PNNs display persistent ocular matrix (ECM) plays a crucial role in terminating cortical plastic- dominance plasticity (Carulli et al., 2010). Some of the inhibitory ity (Silver and Miller, 2004; Laabs et al., 2005). Major compo- effects of CSPGs appear to be mediated through the Rho/ROCK nents of the ECM in the brain are proteoglycans consisting of a pathway (Monnier et al., 2003). Furthermore, there are numer- ous mechanisms by which the GAG chains may interact with Received May 11, 2012; revised Oct. 3, 2012; accepted Nov. 1, 2012. growth-inhibitory molecules, as well as cell surface receptors Author contributions: J.W.F. and F.S. designed research; V.V. and J.C.F.K. performed research; V.V., J.C.F.K., and (Properzi and Fawcett, 2004; Sharma et al., 2012). F.S. analyzed data; J.W.F. and F.S. wrote the paper. These findings suggest that a breakdown of CSPGs may re- This work was supported by UK Medical Research Council Grant G0502299. Chondroitinase ABC was a gift from Acorda TherapeuticsInc.(Hawthorne,NY).WearegratefultoClareGaltreyandWenjunJinforhelpwithsomeoftheexperiments. duce inhibition of neurite outgrowth and permit formation or J.W.F.isamemberoftheScientificAdvisorNetworkofAcordaTherapeuticsInc.whosuppliedthechondroitinase. rearrangement of synapses. Indeed, degradation of CSPGs by the This article is freely available online through the J Neurosci Author Open Choice option. bacterial enzyme chondroitinase ABC (ChABC), which cleaves Correspondence should be addressed to Frank Sengpiel, School of Biosciences, Cardiff University, Museum Ave- the GAG chains, promotes functional recovery after spinal cord nue, Cardiff CF10 3AX, UK. E-mail: [email protected]. V. Vorobyov’s present address: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia. injury (Bradbury et al., 2002). Similarly, degradation of CSPGs by DOI:10.1523/JNEUROSCI.2283-12.2013 chondroitinase restores experience-dependent plasticity in the Copyright © 2013 the authors 0270-6474/13/330234-10$15.00/0 adult rat visual cortex, such that monocular deprivation (MD) Vorobyov et al. • Role of CSPGs in Cat V1 Plasticity J. Neurosci., January 2, 2013 • 33(1):234–243 • 235 Figure1. ImmunohistochemicalevidenceforCSPGdigestion.Photomicrographsshowcoronalsectionsthroughtheprimaryvisualcortexneartheapexofthepostlateralgyrusofonecatinwhich the left hemisphere, contralateral to the deprived eye, had been injected with chondroitinase ABC. Arrows indicate orientation (D, dorsal; V, ventral; L, lateral). The first two columns show images of the injected hemisphere at low magnification (scale bar, 500 ␮m) and high magnification (scale bar, 50 ␮m). The third and fourth columns show images of the noninjected hemisphere, again at low and high magnification (scale bars, 500 and 50 ␮m, respectively. The top row of images shows the extent of ChABC digestion as revealed by labeling the CSPG stubs with the monoclonal antibody 1B5.While there is very little staining of either neuropil or perineuronal nets in the noninjected hemisphere (right) the injected hemisphere (left) exhibits dense labeling throughout all cortical layers (densest in layer 4; approximate layer boundaries are indicated), as well as intense labeling of PNNs surrounding individual neurons. In contrast, staining for WFA (second row) and aggrecan (third row) both show strong labeling of neuropil and PNNs in the noninjected hemisphere but weak labeling in the injected hemisphere. imposed after the critical period results in an ocular dominance ketamine (20–40 mg/kg) and xylazine (2–4 mg/kg). Atropine (0.2 mg/ shift normally observed only in younger animals (Pizzorusso et kg) was injected intramuscularly to reduce mucous secretion. Dexameth- al., 2002) and rats monocularly deprived during the critical pe- asone was injected subcutaneously to prevent cortical edema. Animals riod recover normal ocular dominance if chondroitinase treated were intubated orally and ventilated artificially with a mixture of N2O:O2 in adulthood (Pizzorusso et al., 2006). To translate these results (60:40) and isoflurane (2.0–3.0%, decreased to 1.2–1.5% during imag- ing). Rectal temperature (37.5–38.0°C), electrocardiogram (150–200 into a potential treatment for humans, we tested this method on beats per minute), and electroencephalogram were monitored through- cats, a species whose visual cortex has a functional architecture out the experiment, and adequate measures taken if any of the values more similar to humans and which develops amblyopia under diverged from the targets. A 4% glucose in saline solution was infused i.v. similar circumstances. We employed optical imaging of intrinsic at 3 ml/kg/hr throughout the experiment. signals, visual evoked potential, and single-cell recordings to as- The previously deprived eye was reopened; atropine and phenyl- sess functional outcomes. ephrine were administered to both eyes, which were fitted with gas- permeable contact lenses to protect them and to focus the animal’s Materials and Methods vision onto the stimulus display, a 21” monitor positioned at a dis- All procedures were carried out in accordance with UK Home Office tance of 50 cm. regulations on animal experimentation [Animals (Scientific Procedures) Optical imaging of primary visual cortex was performed as described Act 1986] and the European Communities Council Directive 86/609/ previously (Bonhoeffer and Grinvald, 1996; Schwarzkopf et al., 2007). EEC. Cats of either sex were raised in a normal 12 h light/dark cycle. At The scalp was incised and retracted; a rectangular craniotomy was per- postnatal days (P)20–25 they underwent monocular deprivation by lid formed above area 17 in both hemispheres. A titanium chamber was suture of
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